Pharmaceutical-Coated Medical Products, the Production Thereof and the Use Thereof

ABSTRACT

This present invention concerns a new combination of balloon catheters and formulations containing active substances that adhere to the surface of the balloon membrane. Furthermore the present invention concerns coating processes for the manufacture of these balloon catheters as well as their use in the treatment and prophylaxis of vascular diseases.

RELATED APPLICATIONS

This application is a Division of and claims the benefit of U.S. patentapplication Ser. No. 14/086,813, filed Nov. 21, 2013, now allowed, whichis a Continuation of U.S. patent application Ser. No. 12/671,910 filedMar. 2, 2010, now U.S. Pat. No. 8,608,689, which is the US nationalstage of International Application PCT/DE2008/001285 filed on Aug. 1,2008 which, claims priority to German Application 102007036685.1 filedAug. 3, 2007. The disclosures of which are herein incorporated byreference in their entirety.

MEDICAL AND TECHNICAL BACKGROUND

Many diseases do not affect the whole organism at the same time, but arerestricted to particular kinds of tissue and are frequently restrictedto certain limited areas of tissue or to certain parts of organs.Examples can be found in tumorous diseases, joint diseases and vasculardiseases, and in particular with solid tumours and arterial vasculardiseases.

Pharmacotherapy of these diseases generally takes place by the oral orintravenous administration of pharmaceutical substances which distributethemselves throughout the whole body and in many cases can causeundesirable effects in healthy tissue and in healthy organs,particularly with severe illnesses. These undesirable effects can limitthe therapeutic applications. Selective treatment of the diseased tissueis achieved by means of specific pharmaceutical substances which bind tothe diseased tissue (e.g. antibodies) during the chosen method ofapplication or by selective administration e.g. by direct application tothe diseased tissue, or by being supplied by a catheter in the bloodvessel that is affected. In cases of selective administration there areproblems which arise because of the mainly short duration of the effectsof the pharmaceutical substances and because of the invasive methods ofapplication, since any repeated administration is out of the question.

Problems for pharmacotherapy are caused by the special method ofapplication and the necessity of achieving a significant prophylactic ortherapeutic effect in one single application. In the past 10 yearssignificant success has been achieved particularly in the treatment ofarteriosclerotic vascular changes. Such changes frequently occur inlocalised areas. They lead to constrictions or occlusions of specificsections of the blood vessels which impair or prevent the supply ofblood to the tissue which lies on the other side of the blockage. Thismainly affects the heart, the legs, the brain, the kidneys andsurgically altered vessels such as dialysis shunts. Narrowing of thesevessels can be treated with a catheter which is introducedpercutaneously and which can be introduced into the relevant bloodvessels without causing a large amount of injury because of its smalldiameter. They mostly contain a balloon in the distal part which isfolded around the catheter shaft and which can be expanded by means of afluid. When it is still folded this balloon is pushed into therestricted part of the blood vessel where it is expanded for a shorttime (ranging from a few seconds to a few minutes) so that the originalvessel lumen is restored and the blood can again pass through theoriginally constricted area.

At the same time a tubular piece of metal mesh (vessel support, stent)can be introduced to support the opened vessel lumen. This can be eithermounted on the folded balloon or it can be released as an elastic,self-expanding stent by means of a special catheter.

While the initial success rate is over 90%—measured by the widening ofthe vessel lumen to approaching the size before the constrictionappeared—with many patients a renewed constriction can occur severalmonths after treatment (restenosis). The most significant cause is fromthe excessive proliferation of cells in the vascular wall triggered byinjuries caused during the violent expansion of the vessel. This affectsthe smooth muscle cells in particular, which do not come to a standstillafter the healing of the original injury. This process could be almostcompletely suppressed in the coronary arteries by coating the stent withantiproliferative pharmaceutical products. A requirement is that thepharmaceutical product is released slowly (i.e. over days and weeks)from a polymer matrix. The disadvantage of coating the stent is thathealing is inhibited from taking place. Thrombi can form on the strutsof the stent as long as they are in direct contact with the blood.Thrombi can lead to a sudden and total vascular occlusion, to infarctionand to death. The struts must therefore become rapidly and permanentlyovergrown by an endothelial layer. This is inhibited by the sustainedrelease of an active substance that inhibits cell proliferation.

There are no controlled studies available for peripheral arteries whichdemonstrate effective prophylaxis of restenosis by coating stents withpharmaceutical products. Certain self-expanding nitinol stents dohowever appear to reduce the restenosis rate to some extent without acoating of a pharmaceutical product being necessary (Schillinger M,Sabeti S, Loewe C et al. Balloon angioplasty versus implantation ofnitinol stents in the superficial femoral artery N Engl J Med 2006; 354:1879-88).

The coating of balloons is described in principle in EP 1 372 737 A. Theactive substance is applied by, for example, immersing the balloon in asolution of the active substance. In WO 2004/028582 A the possibilitiesof coating balloons in various stages of folding are described includingwhen the balloons are preformed.

Constricted arteries, often connected with solid calcification, canmainly be expanded to their original lumen only by using a high pressure(8 to 20 atmospheres). This is achieved by using pressure resistantballoons whose diameter does not significantly change with increasinginternal pressure.

The balloon forms a rigid cylinder which lies against the vascular wallas long as the diameter of the vascular lumen before the expansion ofthe balloon is smaller than the diameter of the balloon. With a suitablyhigh pressure an active substance applied to the outside of the balloonis pressed against the expanded vascular wall.

Localised treatment using pharmaceutical substances may also benecessary without stretching the vascular lumen. Examples are thetreatment of arteries following the removal of plaque material withmechanical (e.g. atherectomy catheters), thermal processes (e.g. lasers)or the treatment of changes to the vascular wall which do not lead toflow inhibiting stenoses (e.g. vulnerable plaques, overlying thrombi).Any overstretching and damage to the vessel is undesirable in suchcases. If the customary angioplasty balloons are selected with adiameter which does not lead to any stretching of the vessel then theirmembrane only comes into contact with the irregularly shaped vascularwall in a few places and only transfers the pharmaceutical substance inthose places.

STATE OF THE ART

In WO 02/076509 A it was first disclosed that exposure of the damagedvascular wall lasting a few seconds was sufficient to inhibit arestenosis from developing over a period of several weeks. The same wasdescribed with a balloon catheter coated with a pharmaceutical productwhich on contact with the vascular wall released the active substance inan immediately bioavailable form.

In several earlier and later patent applications the coating of ballooncatheters with pharmaceutical products is described where continualattempts were indeed made to achieve sustained levels of the activesubstances despite the short time the angioplasty balloon was in contactwith the vascular wall. The methods of coating that were generallydescribed produced products that demonstrated a significant lack ofquality and/or which were expensive and time-consuming to manufacture.

Lipophilic, active substances which were slightly soluble in water werepreferred over hydrophilic active substances, because lipophilicsubstances are easy to apply using highly volatile organic solvents. Itis not so easy for them to be prematurely washed away from the surfaceof the balloon during the handling of the devices and when they are inthe bloodstream. They are also more rapidly absorbed by the cells andremain there for longer. In individual cases hydrophilic activesubstances such as methotrexate or arsenic trioxide have been used onstents to inhibit restenosis by neointimal hyperplasia (US 20060348947;Yang W, Ge J, Liu H et al. Cardiovascular Research 2006; 72:483-493).The active substances are embedded in water insoluble polymers fromwhich they are only released slowly. In this way premature loss of theactive substance is inhibited. The same is true for the use ofhydrophilic cytostatics for the antimicrobial coating of indwellingcatheters and other implants (WO03099346).

In fact only the catheter coatings disclosed in WO 02/076509 A and WO2004/028582 A led to effective products which reduce the extent andfrequency of restenosis following vascular dilatation (Scheller B,Hehrlein C, Bocksch W, Rutsch W, Haghi D, Dietz U, BOhm M, Speck U.Treatment of Coronary In-stent Restenosis with a Paclitaxel-coatedBalloon Catheter. N Engl J Med 2006; 255: 2113-2124, Tepe G, Zeller T,Albrecht T, Heller S, Schwarzwälder U, Beregi J-P, Claussen C D,Oldenburg A, Scheller B, Speck U. Local delivery of paclitaxel toinhibit restenosis during angioplasty of the leg. N Engl J Med 2008;358:689-699).

In documents concerning the state of the art technology many activesubstances and matrix substances are named with which coating can becarried out. Preferred among the substances mentioned are those whichinhibit cell proliferation and those which have antiinflammatory oranticoagulant properties.

The additives mentioned were contrast media, matrix or gel-formingadditives e.g. lipids or polymers which are usually used in pharmacy,heparin, castor oil (WO 02/076509) or matrix substances up to 5000 Da,hydrophilic dyes such as, indocyanine green, fluorescein, methyleneblue, sugar, sugar derivates, low molecular weight PEG, organic andinorganic salts, benzoates, salicylates (WO 2004/028582) polymers, alsofor coating of pharmaceutical products (EP 0519063; U.S. Pat. No.5,102,402), polymers such as starch, gelatine, PEG, albumin, chitosan,β-cyclodextrins, hydroxyethyl cellulose as well as lipids, amphiphilicphospholipids and radiocontrast media including amphiphilic iodoxamicacid (DE 102004046244), substances which increase cell permeability suchas linoleic acid, linolenic acid, oleic acid, stearic acid, phenylsalicylate, antioxidants such as vitamin E, tocotrienols, tocopherols,as well as nitrophenyl octyl ether, bis(ethylhexyl)sebacate,diisododecyl phthalate, N-methylpyrrolidone, butylhydroxyanisol,butylhydroxtoluene, phosphorylcholine and polymers (WO 2004/022124);oils, fatty acids, fatty acid esters, contrast medium derivatives, aminoacids, peptides, vitamins, o-phosphoserine, neutral or chargedamphiphilic substances, salts (WO 2007090385);

amphiphilic substances such as polyethylene glycol ester, fatty acidesters of sugars, polyglyceryl-6-fatty acid ester, polyglyceryl-10-fattyacid ester, sucrose monopalmitate, surfactants with lipid chains whichincorporate themselves in lipid membranes, ionic and non-ionicdetergents, substances with more than 4 hydroxyl, carboxyl or aminogroups, sorbitan fatty acid ester, substances with a phenol ring, sodiumcholate, sodium taurocholate; furthermore there are vitamins andderivatives, polyethylene glycol as an additive to a suspension ofpharmaceutical particles: organic acids, salts, anhydrides, amino acidsand peptides including fibrinogen, many functionally defined substancesand coatings (US 2008/0118544). Only a few of these additives are reallyuseful and often this is only for certain active substances andcoatings. Many of the additives mentioned have effects which damage thecell membrane (detergents, amphiphilic substances), inhibit the rapidabsorption of the active substances into the cells or they arethemselves unstable. For the expert it is mainly unpredictable whichadditive is to be used with which active substance and in what dosage.

Possibilities to prolong the release of the active substances aredescribed in detail. Methods of coating the balloons have howeverpreviously received little attention, although this is exceedinglyimportant in order to satisfy the requirements for a product that can bereproducibly manufactured and in order for the product to deposit aneffective dose in the targeted tissue within a period ranging from a fewseconds up to a maximum time of several minutes.

The following processes have previously been described for the coatingof the balloons:

WO 92/11890 A describes the use of microcapsules as carriers of thepharmaceutical product: the microcapsules ensure the prolonged releaseof the active substances. The microcapsules are held in place by meansof a binding agent or by fusion to the surface of the balloon or therecesses in the balloon membrane. Application takes place by immersionor by spraying. Apart from a description of the recesses in the balloonmembrane there are no indications of how a particular active substancecould be applied to the balloon in such a way that that it adheressufficiently securely on the journey through the insertion sheath andthrough fast following blood and for it to subsequently be completelyreleased when the balloon is expanded.

According to WO 2004/006976 A active substances are applied onto a roughor textured balloon surface by immersion, by absorption or by sprayingwhere the balloon is in the expanded state. A hydrophilic layer betweenthe balloon membrane and the lipophilic pharmaceutical product shouldfacilitate the detachment of the active substance.

In WO 00/21584 A pharmaceutical products that are insoluble in water aredescribed as being applied to a balloon by immersion, by spraying or bybeing applied drop wise by means of a pipette. The balloon is coatedwith a polymer which absorbs the active substance. The release wasincomplete during the periods of observation which lasted from minutesto hours.

The preferred placement of the coating under the longitudinal folds ofthe balloon catheter is described in detail in WO 2007090385 whereseveral examples are provided. The mixtures containing the activesubstances are applied beneath the folds by means of processes involvingthe use of pipettes, spraying or injection. While a precise method ofcoating is claimed the examples document that there was widespreadvariation in the doses.

US 2003/064965 A claims a rapid release of pharmaceutical preparationsfrom balloon catheters where the preparations themselves should ensurethat there is a controlled (i.e. prolonged) release. For this purposethe active substances are used in the form of capsules e.g. asliposomes, colloids, microparticles, aggregates or flocculatedsuspensions. Substances proposed for use as matrices are fibrin gels,hydrogels and also glucose. A porous layer should protect the coating.

A protective tube over the coating is also described in US 2006/002973A. The preparations are applied by spraying, immersion, rolling,brushing and by binding to the balloon membranes by the action ofsolvents or the use of adhesives.

Furthermore the following are disclosed as coating processes: sprayingin a vacuum, also using suspensions or emulsions (DE 10 2004 048 265 A),the use of fats and oils (US 2004/224003 A, WO 2003/039612 A), the useof substances or conditions which cause the release of thepharmaceutical product (WO 96/39949 A), the use of lipophilic hydrationinhibitors (WO 2005/089855 A), coating the balloon with preassembledstents (e.g. DE 10 2004 046 244 A; US 2005/0033417 A) and the protectionof the coated balloon by means of coverings which are only retractedshortly before the balloon is expanded.

In EP 1 372 737 A and WO 2004/028582 A processes are disclosed whichdescribe amongst other things coating balloon catheters with lipophilicactive substances which immediately become bioavailable when theballoons are expanded. The coating takes place by immersion, bybrushing, spraying or by using a device for measuring volume.

The importance of the uniformity of the surface coating is taken intoaccount in WO 2004/006976 A by coating the balloon in its expanded statewith all parts of its surface equally accessible from outside. In WO2001/052772 A this problem is addressed for various kinds of product bythe use of a vibrator during the coating process.

With the exception of the coated balloons described in EP 1 372 737 Aand WO 2004/028582 A none of the previously described balloon cathetersproves itself to be effective from a consideration of the improvementsin clinical success achieved, or in terms of the desired biological andtherapeutic targets being achieved from animal experiments alone. Themethods of coating are only described vaguely or the described methodslead to products with considerable shortcomings.

In spite of the very high levels of efficacy the balloon cathetersdescribed in patent specifications EP 1 372 737 A and WO 2004/028582demonstrate disadvantages which are undesirable in a pharmaceuticalproduct. Many of the active substances detailed in all the previouslymentioned patent specifications either do not produce any yield at thesite of pharmacological action, or produce a completely inadequate yieldusing catheters that are coated according to the methods described, orthere are no methods described by which an expert can arrive at a usableproduct that corresponds to state of the art technology. The previouslydescribed coatings of pharmaceutical substances for balloon cathetersare either insufficiently effective or insufficiently reliablyeffective, and amongst other things because the pharmaceuticalsubstances are too unevenly distributed, because they adhere toostrongly or do not adhere strongly enough to the balloon membrane,because they dissolve too quickly or too slowly, or because they containadditives which for their part can damage the vascular wall, or becausethey are too unnecessarily complex in their construction leading todisadvantages in terms of their manufacture, reproducibility, stabilityand application.

Balloon catheters for the transfer of active substances to the vascularwall have not previously been described which do not at the same timecause any overstretching and damage to the vascular wall. If thecustomary angioplasty balloons are selected with a diameter which doesnot produce any stretching of the vessel then their membrane only comesinto contact with the irregularly shaped vascular wall in a few placesand only transfers the pharmaceutical substance in those places.

DEFINITIONS

-   Medicinal product: Instruments for the treatment or prophylaxis of    diseases, and if necessary supported by the use of pharmacologically    effective substances;-   Balloon catheter: A catheter with an expandable distal segment;-   Balloon membrane: A membrane or a balloon membrane characterised by    an outer covering fitted to the catheter balloon which comes into    contact with the vascular wall; preferred membranes are smooth    membranes and membranes which are coated in the folded state; the    balloon catheters which are usually used demonstrate smooth balloon    membranes. The texturising or roughening of the balloon membranes    requires special procedures to be adopted during manufacture;-   Stent: A tubular structure to be placed in cavities or tissues    (vessel supports);-   Active substance: A biological or medically effective substance;    pharmaceutical substances are preferred i.e. permitted active    substances that contain pharmaceuticals;-   Additive: A substance without any intended biological effect;-   Matrix substance: A substance which surrounds an active substance or    holds it firmly in some other way; the matrix itself may display a    biological effect;-   Lipophilic Substance: Affinity to fats; measured as a distribution    coefficient between a solvent that dissolves fats and an aqueous    solvent;-   Hydrophilic Substance: Affinity to water; measured as a distribution    coefficient between a solvent that dissolves fats and an aqueous    solvent;-   Water soluble and/or hydrophilic substances: Biologically effective    substances which either as they are, or in the form of a salt    dissolve at a rate of at least 1 mg/ml (preferably at 5 mg/ml, and    more preferably at 20 mg/ml) in water or an aqueous medium such as    plasma or blood or which demonstrate a distribution coefficient    butanol/water of less than 0.5;-   Sparingly soluble: By the term ‘sparingly soluble’ means that the    solubility in water of the substance concerned is less than 5 mg/ml    and preferably less than 1 mg/m 1;-   Hydrophilic solvents: Solvents in which at room temperature at least    1% by volume of water dissolves and preferably 10% by volume of    water;-   Immediate bioavailability: Transfer of the active substance to the    tissue during the short period of balloon dilatation without the    dissolution of the active substance or its release into the tissue    being delayed by any special treatments like encapsulation;-   Immediate release: Means that when the balloon is expanded the    effective dose of the active substance is released to its    surroundings within a maximum period of 1 minute. The active    substance can, for example, be released in the form of particles and    can then become effective by dissolution in the course of a longer    period of time;-   Low molecular weight: Substances with a molecular weight less than    5000 Da, and preferably <2000 Da, and particularly preferred <1000    Da;-   Hydrophilic/hydrophilised balloon membrane: hydrophilic membranes    consisting of materials which can be wetted with water or with    hydrophilic solvents; hydrophilised membranes are membranes made out    nylon, for example, whose surfaces were changed by subsequent    treatment into a state that can be wetted with water or other    hydrophilic solvents.-   Hydrophilic or hydrophilised membranes are not to be confused with    membranes which are provided with an additional hydrophilic layer;-   Hydrophilically-coated balloon membrane: A membrane, which contains    an additionally applied layer, which can itself be wetted with    water;-   Open on the surface: Pharmaceuticals or additives which are not    incorporated into the balloon membrane or which are not incorporated    into any layers that are firmly attached to the balloon membrane.    For example, they are not incorporated in any polymeric    water-insoluble coatings particularly any hydrogels that may not    become detached. Open on the surface includes coatings which become    covered by the folds in the balloon membrane when it is in its    folded condition;-   Good adhesion: Folded balloon catheters (Orbus IX, Bavaria Medizin    Technologie, Oberpfaffenhofen, Germany, SeQent, BBraun, Melsungen,    Germany balloon size 3.5 mm diameter, 20 mm length or comparable    products from other manufacturers) are coated in the folded state    with 3 μg active substance/mm² according to the dosing procedure    described below. The balloons are expanded when dry and shaken for 5    seconds in a glass vessel. More than 75% of the dose remains on the    balloon;-   Highly volatile: Solvents with a boiling point below 300° C., and    preferably below 160° C., with below 100° C. being particularly    preferred.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing evenness of coating using the Hamilton methodas described in Example 2.

FIG. 2 is a graph showing evenness of coating using the immersion methodas described in Example 2.

FIG. 3 shows an exemplary micro-dosing apparatus of the instantinvention.

DESCRIPTION OF THE INVENTION

The invention has the purpose of making improved medicinal productsavailable e.g. balloon catheters which enable reliable localisedtreatment of diseased tissue to be carried out, new applications to bedeveloped and to facilitate the use of hydrophilic active substancesthat are easily soluble in water.

It is a particular purpose of this present invention to prepare aballoon catheter which does not lead to a stretching or overstretchingof the vessel and yet still releases a sufficient quantity of the activesubstance for the treatment or prophylaxis of diseases of the vascularwall.

This purpose is achieved by the independent patent claims of thispresent invention. Further advantageous embodiments are to be found inthe description, the examples and in the dependent claims. Novel ballooncatheters using a special method of construction are therefore disclosedtogether with methods for coating balloon catheters which are providedin a sufficiently detailed form.

Active Substances and Additives

The following are preferred as active substances:

antiproliferative, antiinflammatory, antiphlogistic, antihyperplastic,antineoplastic, antimitotic, cytostatic, cytotoxic, antiangiogenic,antirestenotic, microtubule inhibiting, antimigrative or antithromboticactive substances.

Examples of antiproliferative, antiinflammatory, antiphlogistic,antihyperplastic, antineoplastic, antimitotic, cytostatic, cytotoxic,antiangiogenic, antirestenotic, microtubule inhibiting, antimigrative orantithrombotic active substances are:

abciximab, acemetacin, acetylvismione B, aclarubicin, ademetionine,adriamycin, aescin, afromoson, akagerine, aldesleukin, am idorone,aminoglutethemide, amsacrine, anakinra, anastrozole, anemonin,anopterine, antimycotics, antithrombotics, apocymarin, argatroban,aristolactam-All, aristolochic acid, arsenic trioxide and othercompounds containing arsenic, ascomycin, asparaginase, aspirin,atorvastatin, auranofin, azathioprine, azithromycin, baccatine,bafilomycin, basiliximab, bendamustine, benzocaine, berberine, betulin,betulinic acid, bilobol, biolimus, bisparthenolidine, bleomycin,bombrestatin, boswellic acids and their derivatives, bruceanoles A, Band C, bryophyllin A, busulfan, antithrombin, bivalirudin, cadherins,camptothecin, capecitabine, o-carbamoylphenoxyacetic acid, carboplatin,carmustine, celecoxib, cepharanthin, cerivastatin, CETP inhibitors,chlorambucil, chloroquine phosphate, cictoxin, ciprofloxacin, cisplatin,cladribine, clarithromycin, colchicine, concanamycin, coumadin, C-Typenatriuretic peptide (CNP), cudraisoflavone A, curcumin,cyclophosphamide, cyclosporine A, cytarabine, dacarbazine, daclizumab,dactinomycin, dapson, daunorubicin, diclofenac,1,11-dimethoxycanthin-6-one, docetaxel, doxorubicin, dunaimycin,epirubicin, epothilone A and B, erythromycine, estramustine, etoposide,everolimus, filgrastim, fluroblastin, fluvastatin, fludarabine,fludarabin-5′-dihydrogenphosphate, fluorouracil, folimycin, fosfestrol,gemcitabine, ghalakinoside, ginkgol, ginkgolic acid, glycoside 1a,4-hydroxyoxycyclophospham ide, idarubicin, ifosfamide, josamycin,lapachol, lomustine, lovastatin, melphalan, midecamycin, mitoxantrone,nimustine, pitavastatin, pravastatin, procarbazin, mitomycin,methotrexate, mercaptopurine, thioguanine, oxaliplatin, bismuth andbismuth compounds or chelates, irinotecan, topotecan, hydroxycarbamide,miltefosine, pentostatine, pegaspargase, exemestane, letrozole,formestane, SMC proliferation inhibitor-2ω, mitoxantrone, mycophenolatemofetil, c-myc antisense, b-myc antisense, β-lapachone, podophyllotoxin,podophyllic acid 2-ethylhydrazide, molgramostim (rhuGM-CSF),peginterferon α-2b, lanograstim (r-HuG-CSF), macrogol, selectin (cytokinantagonist), cytokin inhibitors, COX-2 inhibitor, NFkB, angiopeptin,monoclonal antibodies which inhibit muscle cell proliferation, bFGFantagonists, probucol, prostaglandins,1-hydroxy-11-methoxycanthin-6-one, scopolectin, NO donors,pentaerythritol tetranitrate, syndnoimines, S-nitrosoderivatives,tamoxifen, staurosporine, β-oestradiol, α-oestradiol, oestriol,oestrone, ethinyloestradiol, medroxyprogesterone, oestradiol cypionates,oestradiol benzoates, tranilast, kamebakaurin and other terpenoids,which are used in the treatment of cancer, verapamil, tyrosine kinaseinhibitors (tyrphostins), paclitaxel, paclitaxel derivatives,6-α-hydroxy paclitaxel, 2′-succinylpaclitaxel,2′-succinylpaclitaxeltriethanolamine, 2′-glutarylpaclitaxel,2′-glutarylpaclitaxeltriethanolamine, 2′-O-ester of paclitaxel withN-(dimethylaminoethyl)glutamide, 2′-O-ester of paclitaxel withN-(dimethylaminoethyl)glutamidhydrochloride, taxotere, carbon suboxides(MCS), macrocyclic oligomers of carbon suboxide, mofebutazone,lonazolac, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam,penicillamine, hydroxychloroquine, sodium aurothiomalate, oxaceprol,β-sitosterin, myrtecaine, polidocanol, nonivamide, levomenthol,ellipticine, D-24851 (Calbiochem), colcem id, cytochalasin A-E,indanocine, nocadazole, S 100 protein, bacitracin, vitronectin receptorantagonists, azelastine, guanidyl cyclase stimulator tissue inhibitor ofmetal proteinase 1 and 2, free nucleic acids, nucleic acids incorporatedinto virus transmitters, DNA and RNA fragments, plasminogen activatorinhibitor-1, plasminogen activator inhibitor-2, antisenseoligonucleotides, VEGF inhibitors, IGF-1, active substances from thegroup of antibiotics such as cefadroxil, cefazolin, cefaclor, cefotixin,tobramycin, gentamycin, penicillins such as dicloxacillin, oxacillin,sulfonamides, metronidazole, enoxoparin, desulphated and N-reacetylatedheparin, tissue plasminogen activator, GpIIb/IIIa platelet membranereceptor, factor Xa inhibitor antibodies, heparin, hirudin, r-hirudin,PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase,vasodilators such as dipyramidol, trapidil, nitroprussides, PDGFantagonists such as triazolopyrimidine and seramine, ACE inhibitors suchas captopril, cilazapril, lisinopril, enalapril, losartan, thioproteaseinhibitors, prostacyclin, vapiprost, interferon α, β and γ, histamineantagonists, serotonin blockers, apoptosis inhibitors, apoptosisregulators such as p65, NF-kB or Bcl-xL antisense oligonucleotides,halofuginone, nifedipine, tocopherol tranilast, molsidomine, teapolyphenols, epicatechin gallate, epigallocatechin gallate, leflunomide,etanercept, sulfasalazine, etoposide, dicloxacillin, tetracycline,triamcinolone, mutamycin, procainimide, retinoic acid, quinidine,disopyramide, flecainide, propafenone, sotolol, naturally andsynthetically obtained steroids such as inotodiol, maquiroside A,ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone,dexamethasone, non-steroidal substances (NSAIDS) such as fenoporfen,ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviralagents such as acyclovir, ganciclovir and zidovudin, clotrimazole,flucytosine, griseofulvin, ketoconazole, miconazole, nystatin,terbinafine, antiprozoal agents such as chloroquine, mefloquine,quinine, furthermore natural terpenoids such as hippocaesculin,barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin,agrostistachin, 17-hydroxyagrostistachin, ovatodiolids,4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3 and B7,tubeimoside, bruceantinoside C, yadanziosides N, and P,isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, C and D,ursolic acid, hyptatic acid A, iso-iridogermanal, maytenfoliol,effusantin A, excisanin A and B, longikaurin B, sculponeatin C,kamebaunin, leukamenin A and B,13,18-dehydro-6-alpha-senecioyloxychaparrin, taxamairin A and B,regenilol, triptolide, cymarin, hydroxyanopterin, protoanemonin,cheliburin chloride, sinococuline A and B, dihydronitidine, nitidinechloride, 12-beta-hydroxypregnadien-3,20-dione, helenalin, indicine,indicine-N-oxide, lasiocarpine, inotodiol, podophyllotoxin, justicidin Aand B, larreatin, malloterin, mallotochromanol,isobutyrylmallotochromanol, maquiroside A, marchantin A, maytansin,lycoridicin, margetine, pancratistatin, liriodenine, bisparthenolidine,oxoushinsunine, periplocoside A, ursolic acid, deoxypsorosperm in,psycorubin, ricin A, sanguinarine, manu wheat acid, methylsorbifolin,sphatheliachromen, stizophyllin, mansonine, strebloside,dihydrousambaraensine, hydroxyusambarine, strychnopentamine,strychnophylline, usambarine, usambarensine, liriodenine,oxoushinsunine, daphnoretin, lariciresinol, methoxylariciresinol,syringaresinol, sirolimus (rapamycin), rapamycin combined with arsenicor with compounds of arsenic or with complexes containing arsenic,somatostatin, tacrolimus, roxithromycin, troleandomycin, simvastatin,rosuvastatin, vinblastine, vincristine, vindesine, thalidomide,teniposide, vinorelbine, trofosfamide, treosulfan, tremozolomide,thiotepa, tretinoin, spiramycin, umbelliferone, desacetylvismione A,vismione A and B, zeorin, fasudil.

Preferred active substances that can be applied to the catheter balloonare paclitaxel and other taxanes, rapamycin and other mTOR (mammaliantarget of rapamycin) inhibitors, methotrexic acid, arsenic or arseniccompounds, bismuth or bismuth compounds or thalidomide.

In a further preferred embodiment at least one active substance ispresent as a neutral substance which is sparingly soluble in water, as asalt which is sparingly soluble in water or as an acid which issparingly soluble in water.

As hydrophilic additives the following are used: preferably volatilehydrophilic solvents or hydrophilic solvent mixtures as well asnon-volatile substances which do not have any intended biologicaleffects in the form in which they are administered such as sugar, sugaralcohols, amino acids, fats, inorganic or organic salts and/or contrastmedia or dyes that are suitable for intravascular application.

Preferred additives are ascorbic acid, urea, polyethylene glycol 8000and, despite their poor solubility in water, also triglycerides inparticular triglycerides that are solid at room temperature such astrimyristin.

Balloon Catheter for Coating

In the patent specifications mentioned above then usually smooth walledballoon catheters for percutaneous transluminal angioplasty aredescribed, consisting of various materials such as nylon, PEBAX,polyethylene and many others which are disclosed in DE 10 2004 046 244and in other patent specifications or there are balloon cathetersprovided with grooves or with pores, in which the active substance isplaced, or there are balloon catheters with texturised and roughenedmembranes. The aim of the structural changes with regard to an increasein surface area is to increase the loading with active substances or toimprove the adhesion of the active substances to the balloon.Furthermore in WO 2004/006976 balloons are described coated with anadditional hydrophilic layer. The balloons of these catheters areexpandable up to a predetermined size and should preferably be pressureresistant in order to be able expand stenotic arteries back to theiroriginal diameter.

The texturising of the surface does however have the disadvantage ofdelaying the release of the active substance when the balloon isexpanded in the vessels. In their expanded state the balloons completelyblock the flow of blood through the vessels being treated. A blockage ofthe flow of blood is only tolerated for a very short period of time,particularly in the coronary arteries. The effective dose must bereleased during this time. Every delay in the detachment of at least oneactive substance from the balloon membrane is a disadvantage.

Surprisingly it was found that hydrophilic or hydrophilised balloonmembranes could be reproducibly and evenly coated with activesubstances. In addition a wide range of solvents were suitable forcoating and that a minimum of one active substance adhered to theballoon membrane perfectly. This is particularly true for the case whenthe balloons are coated in a ready folded condition. Hydrophilic balloonmembranes are known and are used to improve the ability of the catheterto slide before the balloon is expanded.

This present invention therefore concerns a balloon catheter thatincludes a catheter balloon with a catheter membrane where the balloonmembrane is hydrophilic or hydrophilised and/or the surface of theballoon membrane has a hydrophilic coating. This hydrophilic coatingpreferably adheres strongly to the surface of the balloon i.e. it issecurely attached to the surface of the balloon and does not becomedetached when the balloon is dilatated.

This present invention also concerns balloon catheters that include acatheter balloon with a hydrophilic or hydrophilised balloon membranewhere the balloon membrane is coated with at least one active substancelying open on its surface which is coated in such a way that at leastone substance is immediately released when the catheter balloon isexpanded. Furthermore the catheter balloon can additionally be coatedwith additives if required.

The hydrophilic surface of the balloon, or the hydrophilically coatedsurface of the balloon, or the surface of the balloon membrane that isprovided with a firmly adhering hydrophilic coating is preferably coatedwith at least one hydrophilic active substance, or with at least onehydrophilic active substance together with at least one hydrophilicadditive.

Preferred catheter balloons according to the invention thereforedemonstrate two coatings, a lower hydrophilic coating which adheressecurely and an outer detachable coating made from one active substanceor from a mixture containing at least one active substance.

It is furthermore preferred when the generally lipophilic balloonsurface is treated with active oxygen to make it hydrophilic. Thehydrophilic membrane or more specifically the hydrophilic surface of theballoon membrane (i.e. the hydrophilic surface of the balloon) can beproduced by a hydrophilic coating on lipophilic balloon membranes (orthe lipophilic surfaces of the balloon) or by being chemically changed(e.g. by reaction with active oxygen) to a lipophilic membrane. Thislatter method is preferred for coating purposes.

Hydrophilic catheter balloons can be coated with simple processes whichuse a coating mixture, such as immersion, to produce coatings that arevery reproducible, so that the active substance content on the catheterballoon which is coated with at least one active substance demonstratesan average standard deviation of less than 20%, preferably less than15%, more preferably less than 10% and even more preferably less than5%.

In a further preferred embodiment the balloon membrane or thehydrophilic balloon membrane or the hydrophilically coated balloonmembrane is coated with at least one hydrophilic active substance whichif required is present in the mixture with at least one slightly watersoluble additive. This embodiment offers the advantage that the slightlywater soluble additive inhibits premature detachment of the activesubstance.

By coating with active substances or additives the improved ability ofthe hydrophilic balloons to slide is lost, at least when the coating isalso situated on the outside of the non-expanded balloon. Hydrophilicballoons have the disadvantage that when they are expanded inconstricted arteries they slip out of the desired position more easily.According to our own observations this disadvantage is largely overcomeby coating using pharmaceuticals and matrix substances, because thecoating that is then released into the surrounding medium noticeablyincreases the friction between the balloon and the arterial wall.

The usual angioplasty balloons should not overstretch the vessels. Theytherefore achieve a certain diameter with a low pressure which cannotsignificantly be increased by increasing the pressure.

A further useful modification to the balloon membrane concerns itsmechanical properties. To transfer the active substance to the vascularwall without overstretching it, membranes are selected which are soft orcompliant and which are expandable at low pressure, or whichsignificantly exceed the diameter of the vessels.

Significantly exceed means that the diameter of the balloon preferablyexceeds the reference diameter of the vessel by at least 20% and morepreferably by more than 30% where the balloon preferably is stretchedwith not more than around 2000 hPa. These balloons are not intended tosignificantly widen the vascular lumen by means of pressure on thevascular wall. A significant widening of the lumen is specifically theremoval of an occlusion or a high grades stenosis, or the widening ofthe lumen by more than 30% of the reference diameter of the vessel. Themembrane properties can be achieved by the informed selection by anexpert of the composition of the membrane and/or the strength of itswalls and the folding. The balloons can have a comparatively lowbursting pressure e.g. equal to or less than 10,000 hPa (9.87atmospheres; [1 atmosphere=1013 hPa]), preferably equal to or less than5000 hPa (4.93 atmospheres), because they cannot be expanded with highpressures. Preferred expansion pressures are preferably below 4000 hPa(3.95 atmospheres), more preferred under 2000 hPa (1.97 atmospheres) andeven more preferred is under 1000 hPa (0.97 atmospheres) above normalpressure. Pressures between 2000 hPa (1.97 atmospheres) and 200 hPa(0.20 atmospheres) above normal are particularly preferred. Cathetersfor the treatment of arteries, veins or dialysis shunts preferably havea diameter to length ratio of less than 0.2, and more preferable is adiameter to length ratio of less than 0.1.

The described balloons should not be confused with balloons which, forexample, are made from silicon or latex, are generally more spherical inshape and are used to anchor catheters in cavities such as the bladderwithout completely filling the cavity concerned.

According to the invention balloon catheters are also preferred whichalready achieve their maximum diameters in their expanded condition atlow pressures and which still possess a certain flexibility in order toadapt to an uneven vascular wall. It is therefore preferred when afterit has been completely unfolded using an increase in pressure that theradius of the catheter balloon increases by more than 15%, preferablymore than 30% and even more preferably by more than 60%. The increase inpressure takes place by introducing a gas (e.g. carbon dioxide) or afluid, for example a contrast medium, into the catheter balloon in theusual manner.

Furthermore balloon catheters are preferred in which, after they havebeen completely unfolded by increasing the pressure inside the catheterballoon, the radius of the catheter balloons increases by more than 15%,more preferably by more than 30% and even more preferably by more than60%.

A further embodiment of this present invention deals with a ballooncatheter with at least one active substance open on the surface which isimmediately released when the balloon is expanded where after theballoon has completely unfolded by increasing the pressure inside thecatheter balloon, the radius of the catheter balloons increases by morethan 15%, more preferably by more than 30% and even more preferably bymore than 60%.

The active substance or active substances and if required furtheradditives adhere to the balloon membrane and/or despite its lack ofrigidity are surprisingly well protected from being prematurely detachedbecause of its structure or because of the folding of the ready to useballoon. The structure of the balloon membrane in the contracted ornon-operational position i.e. without the balloon membrane beingexpanded can contain recesses, depressions and embossments or foldswhich become flattened during expansion under low pressure because ofthe flexibility and elasticity of the membrane. The use of theseballoons is particularly advantageous in the treatment of changes to thevessels which do not significantly restrict the flow of blood i.e. theyconstrict the free vascular lumen by less than 50%. They permit thetreatment of less pressure resistant vessels, because at a low pressurethey are able to position themselves against an irregular vascular wall.Balloon catheters according to this invention are particularly suitablefor the treatment and prophylaxis of vascular diseases and in particularfor inflammatory vascular changes, vulnerable plaque, sections ofvessels that had previously been treated either surgically ormechanically, extensive lesions without the necessity of (a renewed)stretching. It is also suitable for narrow vessels which areinaccessible to stents. Balloon catheters according to this inventionare pre-eminently suitable for the treatment of changes to the vascularwall which do not restrict the flow of blood.

Coating

One of the previously unsolved problems is to distribute an acceptablyaccurate dose of the active substance sufficiently evenly on the surfaceof the balloon. In the administration of pharmaceutical products thereare stringent requirements concerning the accuracy of the dosage of thepharmaceutical form, which is, in this case, the coating of the balloon.While accurate dosing procedures are well known in pharmacy, in mostpharmaceutical applications there is no necessity to distribute activesubstances evenly across a surface. In addition the usual dosingapparatus used in pharmacy and biochemistry mainly operate using aqueoussolutions where the vapour pressure of the dose does not significantlycause any difficulties.

In the patent specifications described below there are some vagueindications of how this problem could be solved. The significance of theproblem is however not recognized. In particular no processes weredescribed which would enable the expert to coat balloons in aneconomical and reproducible manner so that the products are reliablyeffective in releasing the pharmaceuticals rapidly and completely at thesite of pharmacological action.

The coating processes disclosed in EP 1 372 737 A and WO 2004/028582 Ainvolving the repeated immersion of ordinary ready-to-use balloons (whenfolded) in less viscous solutions of lipophilic pharmaceutical productsand suitable additives have produced a dose on the balloon which in thefirst instance was sufficiently reproducible for medical use. Oneimportant insight was that despite the inhomogeneous distribution of theactive substances on the balloons in a radial direction, which wascaused by the folding of the balloon, on expansion of the balloon aneven distribution of at least one active substance is produced on theballoon (Scheller B, Speck U, BOhm M. Prevention of restenosis—isangioplasty the answer? Heart 2007; 93:539-541). A series ofdisadvantages was however evident in their routine use for production.

The process is inconvenient and time consuming because it requiresrepeated immersions, with drying processes taking place in between theimmersions. The amount of active substance adhering to the balloons isdetermined by a number of not always controllable factors. While thecoating of almost identical balloons from one batch was largelyreproducible to a satisfactory standard, this did not always apply tobatches from different production runs. A further problem that isdifficult to solve in an immersion process is the longitudinaldistribution of the active substances. In particular there is thepossibility that the proximal section of the balloon is not sufficientlywell coated. Finally measures are necessary in the process mentioned toprevent the penetration of the less viscous solution into the centrallumen of the catheter. The remaining previously known coating processesprovide even more unfavourable results. A coating of expanded balloonshad the result that the balloons had to be folded with the coating inplace. From a consideration of the dosage applied this is onlyrealisable in any way that is reasonably free from losses when thecoating adheres firmly. A coating that adheres firmly is not releasedsufficiently during the short period of time when there is contactbetween the balloon membrane and the vascular wall. When folded balloonsare coated by spraying the active substance is located only on thesurface of the balloon which leads to increased losses when the ballooncatheter is introduced through the insertion sheath, through the guidecatheters and through the preceding blood vessels. Spraying, brushingand pipetting ensure neither a reproducible dose that can be accuratelypredetermined nor the even distribution of an active substance on thecatheters. With the usual pipettes the exact measurement of the verysmall volumes that are necessary from the preferred highly volatilesolvents is just as difficult as the even distribution of solution ontothe balloon. The advantage of the process described in WO 2007/090385 isthe placing of the active substances underneath the folds of theballoon.

A process according to the invention for coating medicinal products orparts thereof (e.g. balloons at the distal ends of catheters) includesthe following stages:

-   a) preparation of a catheter balloon,-   b) preparation of a micro-dosing unit containing a coating mixture    which does not come into contact with a gaseous phase,-   c) uniform coating of the catheter balloon with the coating mixture    using the micro-dosing unit and without any losses.

In the coating mixture there is generally a coating solution or acoating fluid where a gel, a suspension, emulsion, dispersion or slurrycan however also be used.

During the coating it is important that the solvent from the coatingsolution cannot evaporate before it is applied to the balloon. Thesolvent must not be in contact with any gaseous phase, whose volumecould affect the dose that is administered.

The catheter balloon is preferably mounted horizontally during thecoating stage and is rotated about its longitudinal axis while themicro-dosing unit moves to and fro along the longitudinal axis of thecatheter balloon in order to achieve the complete coating of the foldedor not completely unfolded balloon.

A syringe (see FIG. 3) a cannula, a tube or some other device can beused as a micro-dosing unit that is precise enough for theadministration of the necessary small amounts onto the catheter balloonand which does not damage the catheter balloon during the coating andpreferably does not touch it at all.

It is preferable that highly volatile solvents or chlorine compounds orfluorine compounds with a boiling point below 300° C. are used, and morepreferably with a boiling point below 100° C. are used as solvents forthe coating mixture. Furthermore hydrophilic solvents or mixtures of atleast one solvent or hydrophilic solvent with water can be used.

The balloons are preferably coated in their folded form, but can howeveralso be coated in any other form using a suitably adapted device.

In order to achieve an even coating, the entire membrane from proximalto distal including all the folds should be simultaneously wetted withthe coating mixture during the coating process. This should however takeplace without any dripping of the coating mixture.

A gel can also be used as the coating mixture. Here at least one of theactive substances can itself function as the gelling agent or take partin gel formation. The active substance itself can function as a gellingagent if a gel like coating mixture is obtained, without any further gelforming substances being present beside the active substance.

In addition it is preferred that at least one active substance isapplied to the catheter balloon in a form which is sparingly soluble inwater.

As an alternative at least one active substance that may be readilysoluble in water i.e. is hydrophilic can be changed into a sparinglysoluble form after it has been applied to the balloon. This can occur,for example, by complexing with cyclodextrins or by salt formation. Themanufacture of a salt that is sparingly soluble in water and theselection of a counterion or complex forming agent are part of thestandard knowledge possessed by an expert and can be determined bysimple tests of solubility.

A preferred embodiment of the coating process according to the inventionis described in the following section and includes:

A) the Preparation:

-   -   1) selected balloon catheters or suitable components that        contain the balloon, where the balloon is preferably in the        folded condition or in a condition with preformed folds, which        are not however pressed tightly together.    -   2) a device to hold the balloon preferably in a horizontal        position where the balloon in a preferred embodiment can be        rotated around its longitudinal axis    -   3) a device for measuring microvolumes for the administration of        solutions preferably containing highly volatile organic solvents        in which the volume to be administered does not come into        contact with any gaseous phase which could affect the dose        administered.    -   4) a component designed to transfer the liquid from the volume        measuring device to the balloon.    -   5) a solution containing at least one active substance and        optionally one or more additives.

B) The Work Stages:

-   1) calculation of the necessary volume for the coating of the    balloon at the desired dosage using the known surface of the balloon    in mm² and the concentration of the active substance in the    substance-   2) introduction of the catheter or the part of the catheter that    holds the balloon into the mounting-   3) calibration of the volume measuring device for the calculated    volume of the solvent being used-   4) filling of the volume measuring device with the coating solution    which takes place without any bubbles of gas being present-   5) continual slow rotation of the balloon about its longitudinal    axis-   6) positioning of the component for transferring liquid with the    opening through which the solution exits either located on the    balloon or just above the balloon, or directly below the balloon or    to one side of the balloon-   7) transfer of the intended volume of coating solution onto the    balloon while the component for transferring liquid is moved with a    steady speed backwards and forwards along the cylindrical part of    the balloon in the direction of the longitudinal axis. The speed of    transfer of the solution is preferably to be adjusted so that all    parts of the balloon are wetted with the liquid at the same time    without any drops forming on the balloon which could fall off.

The volume measuring device ensures an accurate dose on the balloonindependent of the balloon material and its surface structure (smooth ortexturised), independent of whether it is tightly folded or looselyfolded or whether it is partially or completely expanded, independent ofthe size and the type of balloon and of the individual batches ofballoons used. The movement of both the balloon and the component fortransferring liquid combined with the complete wetting of the balloonusing the coating solution does however effect a surprisingly uniformdistribution even on long stretched balloons.

After coating the balloons can under suitable conditions be ready foldedand/or dried, stents can be assembled and the catheters packed andsterilised in the usual way.

The principle described above for coating can be realised by an expertusing various items of equipment and different devices in various wayswhich can be matched to the needs of the objects that require coating.They are characterized by the accuracy of the dosage and the placementof the dose, the uniformity of distribution of the coating on thesurface of the area to be coated including the penetration of themixture into the folds and other not readily accessible structures. Itis simple and cost-effective to manipulate, because the amount ofmaterial needed and the amount of time needed are both minimal; theprocess is also easy to control and can be automated. In particular theloss of the coating mixture in containers and as a result of anyunwanted distribution of the mixture onto the medicinal product or ontoits surroundings is avoided. Any change in the coating mixture beforethe application to the medicinal product by premature evaporationsolvents is impossible.

Accelerated Dissolution and Detachment of Lipophilic Active Substances

A series of solvents for the coating of medicinal products withpharmaceuticals are described in EP 1 372 737 A and WO 2004/028582 A, inU.S. Pat. No. 6,306,166 and in other specifications. It was surprisinglyfound that lipophilic pharmaceutical products, for example not onlypaclitaxel and other taxanes, but also rapamycin and related substancesbecome particularly easily detached from the balloon surface in aqueousmedia, blood or tissue and go into solution when the coating of themedicinal products is carried out with solutions of substances inchloroform or dichloromethane or other highly volatile chlorine andfluorine compounds.

Further suitable measures for accelerating the detachment of lipophilicactive substances and/or active substances that are sparingly soluble inwater are the use of volatile hydrophilic organic solvents particularlymethanol, ethanol, propanol, formic acid, acetic acid, tetrahydrofuran(THF), acetone, 3-pentanone, esters of carboxylic acids in particularmethyl formate, ethyl formate, methyl acetate, ethyl acetate etc. andmixtures of these substances with water. One particularly preferred formof coating with, for example, paclitaxel does without any additionalcoating of the original balloon membrane with other polymers, hydrogelsor other carrier layers for pharmaceutical products, for all additivesand for complex mixtures of solvents. Such coatings have previouslyproved to be largely ineffective (Scheller B, Speck U, Abramjuk C,Bernhardt U, BOhm M, Nickenig G: Paclitaxel balloon coating—a novelmethod for prevention and therapy of restenosis. Circulation 2004; 110:810-814, WO 2004/028582, example 7; Cremers B, Biedermann M, Mahnkopf D,BOhm M, Scheller B. Paclitaxel-beschichtete PTCA-Katheter: Gibt esUnterschiede? Einfluss von PACCOCATH®- and DIOR®-Ballonkathetern auf dieNeointimaproliferation an Schweinekoronarien (Paclitaxel coated PTCAcatheters: are there any differences? The effect of PACCOCATH® and DIOR®balloon catheters on neointimal proliferation in coronary arteries inpigs) Clin Res Cardiol 2008; 97-Suppl 1: V1742).

Surprisingly the crystal structure and the adhesion of paclitaxel to theballoon membrane is able to be very precisely controlled by the additionof a small amounts of water to a solution of paclitaxel in, for example,isopropanol, tetrahydrofuran, dimethylformamide or acetic acid ormixtures containing these solvents. Preferred solvents are (a) thosethat lead to a very strong adhesion of paclitaxel to the balloonmembrane and (b) those that dissolve at least one percent by volume ofwater at room temperature. From these simple solvent mixtures crystalsof the active substances are formed without any technological outlay. Inone specific case paclitaxel crystals are formed which adhere stronglyto the folded balloon. When the balloon is expanded, for example inconstricted arteries, they are almost completely detached and are to alarge extent transferred to the tissue.

The crystals slowly dissolve there—as is known from pharmacy—and over acertain period of time this ensures that there is an effectiveconcentration of pharmaceutical product. The application to the balloonis significantly more straightforward using the dosing process describedabove. With regard to the dosage it is more accurate than that describedin WO 2007/090385. Not having a matrix substance has the great advantagethat the compatibility of the matrix with the active substance, its longterm stability, its effect on the balloon membrane and its biologicaltolerance do not have to be tested. Additives can affect the adhesion ofpreassembled stents, for example when the adhesion is reduced and thestent is prematurely lost or when the adhesion is increased and thestent is not released from the balloon after expansion; in both casesthe patients are endangered. The reduced load on the balloon by nothaving an additive is also advantageous because the additionally appliedsubstance makes the necessary tight folding of the balloon moredifficult. A smaller external diameter is necessary for the balloons topass through narrow stenoses.

Further embodiments according to this invention concern catheterballoons with a smooth walled membrane that is coated with an activesubstance dissolved in an organic solvent which contains at least 1%water, preferably at least 10% water, which is then dried and sterilisedand in which the active substance is present in a crystalline form. Hereit is preferred that the catheter balloons with smooth walled balloonmembranes are coated in the folded condition.

A further preferred embodiment of this present invention concerns theballoon catheter in which the balloon membrane of the catheter balloonthat is coated with an active substance dissolved in an organic solventwhich contains at least 1% water, preferably at least 10% water, whichis then dried and sterilised and in which the active substance ispresent in a crystalline form.

A further preferred embodiment of this present invention thereforeconcerns the balloon catheter where the balloon membrane of the catheterballoon is smooth walled and is coated with paclitaxel crystals that lieopen on the surface, without any additives and coated in a manner inwhich when the folded balloon is introduced into an artery at least 70%of the paclitaxel, preferably at least 80% and more preferably at least90% of the paclitaxel remains adhering to it and where when the catheterballoon is expanded in a restricted artery it is immediately released.

Soluble, water-soluble or micro-particular matrix substances can beadded to the liquid preparations for coating, as is already known, wherethe particular matrix substance can also be the active substance itself.The selection of a suitable additive is in most cases dependent on theactive substance, the solvent and the surfaces of the balloons. Examplesof suitable additives that encourage detachment of the coating areascorbic acid, urea and polyethylene glycol preferably in the molecularweight range from around 5000 to 20,000 Da. On account of theunfavourable effect of the loading on the diameter and flexibility ofthe coated balloon the total loading of the balloon (active substanceand additive) i.e. the total dose of all non-volatile components appliedto the balloon membrane should preferably be below 10 μg/mm² and morepreferably below 5 μg/mm² balloon surface in the expanded state andadditives should be applied at a rate of preferably below 1 μg/mm²balloon surface and more preferably below 0.3 μg/mm².

The present invention further concerns a balloon catheter in which theballoon membrane of the catheter balloon is coated with at least oneactive substance lying open on the surface and either ascorbic acid orurea or a sold triglyceride at room temperature like trimyristin orpolyethylene glycol in the molecular weight range from 800 to 20,000daltons, or any preferred mixture of the these in a manner in which atleast one active substance is immediately released when the catheterballoon is expanded.

Water Soluble and/or Hydrophilic Substances

Previously there were two different classes of compounds for thelocalized treatment and prophylaxis of arterial diseases: ‘ . . .hydrophobic drugs, which are retained within tissue and have dramaticeffects, and hydrophilic drugs, which are rapidly cleared andineffective’ (Levin A D, Vukmirovic N, Hwang C-W, Edelman E R. Specificbinding to intracellular proteins determines arterial transportproperties for rapamycin and paclitaxel. PNAS 2004; 101:9463-9467).

In U.S. Pat. No. 6,306,166 it was explicitly stated that it was mainlyactive substances that were insoluble in water that were selected foruse in coating. For example the coating of stents with insufficientlylipophilic substances had proved ineffective for restenosis prophylaxis(Muni N I et al. Am Heart J 2005; 149:415-433; Kiesz R S et al.Circulation 2001; 103:26-31; Kutryk M J B et al. J Am Coll Cardiol 2002;39:281-7). Huang y et al. Am J Cardiol reported about a slightinhibition of neointimal proliferation using stents coated withmethotrexate which slowly released the active substance from a polymer.The use of methotrexate for coating catheter balloons isdisproportionately more difficult, because the water soluble activesubstance dissolves quickly, even before the balloon has reached thestenosis in the blood vessel. For arsenic trioxide efficacy after theslow release from a polymer matrix was also described (Yang W, Ge J, LiuH et al. Cardiovascular Research 2006; 72:483-493). The restriction ofpharmaceutical products to lipophilic substances places undesirablelimits on selection with regard to efficacy, activity profile andavailability. It is indeed from the water soluble, less lipophilicsubstances that extraordinarily effective active substances can befound. Despite their completely different physicochemical andpharmokinetic properties it was surprisingly found that like lipophilicpharmaceutical products water soluble and/or hydrophilic activesubstances could cause long lasting effects from an exposure of cellslasting only a short period of time. Surprisingly there was no need tocompensate for the rapid dilution of these substances by means ofsustained release from a reservoir implanted for long term use.

Problems that are difficult to solve arise from the use of hydrophilic,mainly readily water soluble pharmaceuticals for administration by meansof coated medicinal products, particularly balloon catheters. Sparinglywater soluble substances such as paclitaxel or rapamycin and itsderivatives largely continue to adhere to the surface of the coatedmedicinal products when they are placed in insertion sheaths, in guidecatheters and in the blood; they only become detached from the vascularwall under mechanical stress e.g. by the expansion of the balloon and byrubbing against the vascular wall and if necessary they can be dissolvedin the presence of proteins and membrane lipids Hydrophilic substanceson the other hand dissolve on the first contact with water or with bloodand are lost to a great extent before they reach the targeted location.Hydrophilic substances therefore generally need protective measures tobe taken to inhibit their release when they are used during the shorttime that elapses between the first contact of the sterilized medicinalproduct with aqueous liquids (with blood for example) before arriving atthe targeted location and the actual arrival at the targeted locationitself.

These measures should not be confused with formulations which effect adelayed release of the active substance at the site of pharmacologicalaction in order to ensure that the effects last over a longer period oftime. The release of hydrophilic, water soluble active substances shouldtake place immediately the active substance has reached the site ofpharmacological action and should not take place earlier.

A surprising anomaly is shown by arsenic trioxide despite itshydrophilic character. It can be applied on the balloon surface as asolution, but does however adhere strongly to the membrane after dryingand is almost completely released on expansion.

The problem with hydrophilic and/or water soluble active substancesbegins with the application onto the surface of the medicinal products.Many of these surfaces, in particular the catheters which are usuallyused only allow themselves to not be wetted, or else to be very unevenlywetted by aqueous or other hydrophilic solvents. A further significantproperty is the adhesion of the coating to the surface of the medicinalproduct or specifically the balloon membrane. The evenness ofdistribution of the coating and its adhesive properties are surprisinglyclearly influenced by slight changes to the surface. Surfaces that aretreated with activated oxygen (‘plasma’) therefore not only demonstratean even distribution but in particular they also show very good adhesionto the folded membrane and very good detachment of the coating from theballoon when it is expanded. Similar results are obtained withhydrophilically derivatised or hydrophilically coated membranes.

Water is only suitable for use as the solvent for the application ofhydrophilic and/or water soluble active substances to a limited extent.Relatively hydrophilic organic solvents such as methanol, ethanol,propanol, isopropanol, dimethylsulfoxide, acetone, formic acid, aceticacid, ammonia, tetrahydrofuran, dimethylformamide, dimethylacetamideetc., mixtures of these solvents with each other and mixtures of thesesolvents with water where the pH of the solution can be adjusted usingacids and bases. It is preferable that solvents are to be removed beforeuse. The solvents are evaporated as far as possible before the use ofthe medicinal products, if necessary using increased temperatures and areduced pressure.

The hydrophilic and/or water soluble substances can be dissolved as suchor in the form of salts. In the case of anthracyclines, and particularlydoxorubicin, viscous solutions, which are surprisingly well suited tothe coating of surfaces, can be manufactured using a suitable selectionof concentration, ion concentration, preferably the sodium ionconcentration, and pH (Hayakawa E, Furuya K, Kuroda T, Moriyama M, KondoA. Viscosity study on the self-association of doxorubicin in aqueoussolution. Chem. Pharm Bull 1991; 39:1282-1286). Although these solutionscan contain water as the only solvent, very uniform coatings can beobtained even when the membranes are rather lipophilic as used in theusual balloon catheters.

All the coatings mentioned above are applied according to one of theusual processes: by immersion, by spraying, by brushing or by means of avolume measuring device, preferably according to the process describedabove using a volume measuring device. In the case of balloon cathetersthe balloons are coated when expanded, when folded or in someintermediate state.

A further possibility for coating with hydrophilic and/or water solublesubstances is that the substances are not applied to the surface in theform of a solution. Hydrophilic and/or water soluble substances can forexample be applied in the form of microparticles, or nanoparticles inliquids in which they are only slightly soluble or they are precipitatedfrom liquids in which they are soluble. This permits the use oflipophilic organic solvents and the addition of lipophilic additives incombination with hydrophilic and/or water soluble substances. Prematuredetachment of the coating is prevented by coating the surfaces withpreformed particles and if required by the addition of lipophilicadditives in lipophilic solvents.

Many hydrophilic and/or water soluble substances contain functionalgroups which can become electrically charged. They can be soluble inorganic solvents when they are not electrically charged and be used forcoating in this form. They can form readily soluble or sparingly solublesalts. One preferred possibility for coating medicinal products is theuse of sparingly soluble salts of hydrophilic and/or water solublesubstances. In this way premature detachment is avoided followingcontact with physiological solutions which are, for example, used to wetthe catheters or else following contact with blood in insertion sheaths,guide catheters or else direct contact with blood in the blood stream.The efficacy of the pharmaceutical products is not cancelled out by theformation of insoluble salts.

The sparingly soluble salt again releases the unchanged pharmaceuticalsubstance following its detachment from the medicinal product. Thiscompletely satisfies the requirements for the extraordinarily smallamounts of pharmaceutical product which are necessary to be effectivewhen administered locally. The same principle can be used forhydrophilic water soluble additives. The change to a sparingly solublesalt creates a sparingly water soluble matrix structure which protects ahydrophilic and/or water soluble active substance from prematuredetachment for a certain period of time e.g. during the manipulation ofa balloon catheter before the actual dilatation of the vessel and beforethe actual detachment of the substance.

The insoluble salts can be produced before the use of the hydrophilicand/or water soluble substances for coating the medicinal products andcan then be used in the form of suspensions in suitable carrier liquids.A preferred method is to coat the medicinal products with the solubleform in an aqueous solution or in an organic solvent which containswater or in a relatively hydrophilic organic solvent or a solventmixture. The solvent is then evaporated and the surface which has justbeen coated is next treated with a precipitating agent for use with thehydrophilic and/or water soluble substances so that the subsequentchange into the insoluble salt or the insoluble electrically neutralform can take place. The precipitating agent can be applied in anypreferred form e.g. by immersion, spraying, brushing or using a volumemeasuring device.

Examples of physiologically acceptable sparingly soluble salts arecalcium, magnesium, zinc and iron (II) or iron (III) compounds on theone hand and on the other hand there are phosphates, sulphates, oxalatesor also salts of ionic radio contrast media such as diatrizoates.

The present invention therefore concerns the use of at least one lowmolecular weight, hydrophilic active substance in the form of asparingly water soluble salt or as a sparingly soluble water solubleacid or a sparingly soluble base for the treatment and prophylaxis ofvascular diseases and also for the achievement of lasting effects fromone single treatment with immediate bioavailability.

In a further embodiment of this invention the balloon membrane of thecatheter balloon with at least one active substance lying open on thesurface which is coated in such a way that at least one active substanceis immediately released when the catheter balloon is expanded, where atleast one water soluble active substance is present as a salt that issparingly soluble in water or an acid that is sparingly soluble in wateror a base that is sparingly soluble in water or else a complex that issparingly soluble in water.

A similar embodiment of this invention concerns a balloon membrane ofthe catheter balloon with at least one active surface lying open on thesurface which is coated in such a way that at least one active substanceis immediately released when the catheter balloon is expanded, where atleast one active substance has been converted into a sparingly watersoluble form or particularly a salt that is sparingly soluble in wateror a base that is sparingly soluble in water or an acid that issparingly soluble in water or a complex that is sparingly soluble inwater after application to the balloon membrane or the hydrophilicballoon membrane or the hydrophilically coated balloon membrane

The loss of hydrophilic and/or water soluble active substances frommedicinal products during the manipulation of the device, in particularon the way through the insertion sheath or guide catheter to thelocation where the treatment is to take place can also be achieved bythe subsequent coating with physiologically acceptable substances thatare slowly or slightly soluble in water. In so doing these substancescan achieve a desired pharmacological effect or else act as additives.These additional coatings can be solids or else they can be liquids asis the case with certain lipids. Examples of additional coatings whichare solids are sugar, sugar alcohols, other neutral organic substances,lipophilic amino acids, salts of organic and inorganic acids and bases,contrast media that are usually used in medicine or dyes, anticoagulantssuch as heparin, platelet aggregation inhibitors such as acetylsalicylicacid or salicylic acid and many others. The effectiveness of this kindof special additional coating in protecting any given coating is to betested on an individual basis. Additional protective coatings aretherefore preferably applied so that the solutions are made usingsolvents in which protective coating is insoluble. For example,acetylsalicylic acid (as an additional protective coating) is readilysoluble in ethyl acetate in which many hydrophilic and/or water solubleactive substances are very slightly soluble.

Additional protective coatings should be as thin as possible. Anapplication of <30 μg/mm² surface area is preferred.

Additional protective coatings can on the other hand be applied in avariety of ways where the preferred methods are spraying and a verybrief immersion.

In a further preferred embodiment the present invention is thereforeconcerned with balloon catheters which are coated with at least onehydrophilic active substance or a preparation that contains at least onehydrophilic active substance where a further outer protective layer isapplied on top of this coating in the form of a biocompatible materialthat is slightly or only slowly soluble in water.

Balloon catheters are therefore preferred in which at least one activesubstance or at least one hydrophilic active substance is coated with orimpregnated with a layer that is slightly or only slowly soluble inwater. The protective layer can penetrate the layer of active substance.It can for example consist of substances which do not have biologicaleffects, but it can also consist of acetylsalicylic acid or heparin.

EXAMPLES Example 1 Coating of Hydrophilic and Non-Hydrophilic BalloonCatheters with Paclitaxel: Test Nos 102/103 and 128/129

Coating solution: 30 mg paclitaxel/ml in acetone 89%, ethanol 9%,Ultravist®-370 (Schering AG, Berlin) 2%, by immersing it 4 times andallowing it to dry between each immersion:

Number of balloon μg paclitaxel/mm² Type of catheter catheters balloonsurface standard deviation standard, 3.5 to 15 mm 5 3.4 0.5 hydrophilic,3.5 to 5 2.8 0.2 15 mm standard, 3.5 to 20 mm 8 5.0 0.5 hydrophilic 3.5to 20 mm 8 5.6 0.2 Conclusion: balloons with hydrophilic surfaces can bereproducibly coated.

Example 2 Coating with a Micro-Dosing Device: Comparison with Coating byImmersion

In the first series (test nos. 323 and 326-329) each time 3 ready foldedballoons were either immersed 4 times in coating solution A and in eachcase they were thoroughly dried between each immersion, or else theactive substance was applied twice using 12.5 μl of the same solutionand a Hamilton CR-700 constant rate syringe, or 3 further coatingsolutions were applied using highly volatile organic solvents.

Active substance Condition Concentration on the balloon Test no of theof the active Number of coatings μg/mm² (n) Balloon balloon- Solventsubstance by immersion mean ± SD 323 (3) 3.0-17 folded A. 30 mg/ml 4 4.1± 0.7 Number of dosing operations and their volumes 326 (3) 3.0-17folded A 30 mg/ml 2 × 12.5 μl 3.6 ± 0.0 327 (3) 3.0-17 folded B 30 mg/ml2 × 12.5 μl 3.6 ± 0.1 328 (3) 3.0-17 folded C 30 mg/ml 2 × 12.5 μl 3.8 ±0.1 329 (3) 3.0-17 folded D 30 mg/ml 2 × 12.5 μl 3.7 ± 0.0

Applying the dosage using the Hamilton syringe leads to a significantlymore accurate dosage on the balloon.

Uniformity of the dosage was also successful on balloons of differentsizes (tests 390/391) and was more accurate than when coating byimmersion (392).

Active substance Condition Concentration Number of dosing on the balloonTest no of the of the active operations and their μg/mm² (n) Balloonballoon- Solvent substance volumes mean ± SD 390 (4) 3.5-20 folded A 30mg/ml 2 × 14 μl 3.7 ± 0.1 391 (4) 2.0-14 folded A 30 mg/ml  2 × 6 μl 3.6± 0.1 Number of coatings by immersion 392 (4) 3.5-20 folded A 30 mg/ml 44.4 ± 0.4

The distribution of the active substance along the longitudinal axis ofthe balloons was investigated for each of 3×100 mm long PTA balloons of5 mm diameter. The balloons were cut into 10 mm long pieces aftercoating with either the dosing operation using the Hamilton syringe (seeFIG. 1) or by immersion (see FIG. 2). The content of the activesubstance in the pieces of balloon were measured using HPLC. In theillustration a value of 1 on the y axis corresponds to the averagequantity distributed over the entire length i.e. it is a perfectly evendistribution.

The distribution of the active substance on the longitudinal axis of theballoon after application using the dosing operation is in no singlecase more uneven than using immersion, or rather it is in fact moreuniform than immersing the balloon (see FIGS. 1 and 2).

Example 3 Device to Apply the Coating Solution for Use on the Balloon

Preferably using a needle with a narrow lumen which is 2 to 10 cm longwith proximally a connection to the micro-dosing apparatus, the distalend is closed. The needle has an outlet at the side in the form of acurved recess which fits the curvature of the balloon (see FIG. 3).

Example 4 Coating the Balloon Catheters with Methotrexate

Coating solution:

30 mg methotrexic acid+100 μl sodium bicarbonate (7.5%)+900 μl methanol(coating with 2×16 μl, corresponding to ˜4 μg/mm² balloon surface)

Balloons: 3.5 to 19 mm

Additional coat: Ultravist®-370+hydroxyethyl starch (HES) 10% (1:1 byvolume)+30 mg methotrexate/ml applied by immersing for a short timeStents: stainless steel, balloon-expandable 3.5 to 18 mmContent of active substance: 5.3 μg/mm² balloon surface

Example 5

The efficacy and tolerance of coated balloon catheters according toexample 5 in overstretched coronary arteries in pigs

Method: Scheller B, Speck U, Abramjuk C, Bernhardt U, Böhm M, NickenigG: Paclitaxel balloon coating—a novel method for prevention and therapyof restenosis. Circulation 2004; 110: 810-4

Stents were implanted into pigs with the help of methotrexate coated oruncoated (control) balloon catheters. After 4 weeks the extent of theconstriction of the lumen in the area of the stent was measured usingquantitative angiography.

Results:

Control Methotrexate n = 9 n = 8 p Reference diameter [mm] 2.41 ± 0.282.30 ± 0.39 0.495 Stent diameter [mm] 2.64 ± 0.13 2.41 ± 0.29 0.045 Rateof overexpansion [—] 1.11 ± 0.14 1.07 ± 0.20 0.068 Reference diameter28d [mm] 2.35 ± 0.39 2.38 ± 0.26 0.840 Minimum vessel diameter 28d [mm]1.54 ± 0.32 1.74 ± 0.41 0.273 Late lumen loss [mm] 1.10 ± 0.33 0.67 ±0.39 0.025

The late lumen loss means the amount by which the original coronaryartery lumen diameter decreases due to excessive cell growth within 4weeks. With blood flowing through them the original coronary arterylumen diameters were 2.64 mm and 2.41 mm respectively. In the controlgroup (no methotrexate) the late lumen loss was 1.1 mm and in the grouptreated with methotrexate the late lumen loss was 0.67 mm. Methotrexatehas significantly reduced (p<0.025) the unwanted proliferation of thearterial wall which constricted the vascular lumen.

Example 6 Coating of Balloon Catheters with Thalidomide

Falcon Bravo RX 3.5 to 20 mm, Invatec S.R.L., Roncadelle, Italy 8 items;

Coating solution:

Dimethylformamide+50 mg/ml thalidomide

Coat each balloon 2 times with 8 μl and leave to dry for at least 12hours after each coating.

Afterwards immerse 4 balloons for a short time in 50 mg trimyristine in3 ml warm ethyl acetate.

Loss by means of the insertion sheath, the guide catheter and by 1minute in a coronary artery of a pig (not expanded) and then withdrawn.Analysis using HPLC, columns: Waters Symmetry, C18, 5 μm, 25 cm×4.6 mm,mobile phase: 72% by volume 0.01M ammonium acetate buffer pH 5.5 and 28%by volume acetonitrile, 0.8 ml/min; detection: at 300 nm. The balloonstreated with trimyristate lost an average of 28% of the active substanceon the way to the coronary arteries and back, the balloons which werenot treated with trimyristate lost 95% i.e. the trimyristate coating hadsignificantly improved the adhesion of the thalidomide to the balloon.

Example 7 Coating of Balloon Catheters with Arsenic Trioxide

Falcon Bravo RX 3.5 to 20 mm, Invatec S.R.L., Rocadelle, Italy 12 items

Coating solution:

50 mg As₂O₃ are dissolved in 1 ml water for injection; the solution isdiluted with 3 ml acetone or methanol.

Coat each balloon 3 times with 25 μl and leave to dry for at least 12hours after each coating.

Loss by means of the insertion sheath, the guide catheter and by 1minute in a coronary artery of a pig (not expanded) and then withdrawn,or following expansion in a coronary artery for I minute; analysis byatomic absorption spectrometry after ashing.

The balloons lost on average 25% of the active substance on the way tothe coronary arteries and back. After expansion in the arteries onaverage 13% of the dose remained on the balloons (in each case n=4).

Example 8a Control of Adhesion Using Just the Solvent (Series 1)

Falcon Bravo RX 3.5 to 20 mm, Invatec S.R.L., Rocadelle, Italy 12 items

Each balloon was coated in the folded state with 3 to 4 μg/mm²paclitaxel and was tested for loss of the active substance duringexpansion in the dry state as defined under ‘Definitions’.

Acetone 21% Dioxane 12% Dimethylformamide 24% Dimethylsulfoxide 66%Acetic acid 4% Isopropanol 19% Tetrahydrofuran 4%

Example 8b Control of Adhesion Using Just the Addition of Water Up tothe Limit of Solubility for Water in Tetrahydrofuran (THF) at RoomTemperature (Series 2)

Tetrahydrofuran 3% Tetrahydrofuran with 10% water by volume 3%Tetrahydrofuran with 20% water by volume 16% Tetrahydrofuran with 37%water by volume 37%

Example 9 Coating a Balloon Catheter with the Addition of Urea

Falcon Bravo RX 3.5 to 20 mm, Invatec S.R.L., Roncadelle, Italy 8 items;Coating solution:

70 mg urea dissolved in 1 ml water+9 ml tetrahydrofuran+500 mgpaclitaxel Coating each balloon once with 18 μl

1-30. (canceled)
 31. A process for the coating of catheter balloonsincluding the following stages: a) preparing a catheter balloon, b)preparing a micro-dosing unit containing a coating mixture which is notin contact with a gaseous phase, c) coating of the catheter balloon withthe coating mixture using the micro-dosing unit, wherein the coatingmixture comprises at least one active agent and at least one additivecomprising ascorbic acid.
 32. The process according to claim 31, whereinduring coating, the catheter balloon rotates about its longitudinal axisand the microdosing unit moves to and from along the longitudinal axisof the catheter balloon.